Research spotlight: How evolving studies can lead down unexpected paths

Sometimes projects turn out exactly how they were intended to from start to finish. The person running the project decides what they want to do or find out, goes about gathering materials and data and ultimately puts together a finished project that roughly matches the original goal.

This isn't the case for the work of Associate Professor Cheng-Chen Huang from the UW-River Falls biology department. He started out trying to see why a weight loss supplement was causing kidney failure, and he ultimately ended up with a new way to study heart failure drugs and a potential treatment for skin cancer.

Huang initially started his research project in 2005. What he wanted to do back then, he said, was to figure out why a substance called aristolochic acid – which had been used in a weight control food supplement – was causing kidney failure in the people who consumed it.

“That was a very simple kind of idea for this project,” Huang said.

Plenty of other researchers had tried to figure out why aristolochic acid has this effect, but Huang’s approach to the problem was a little different. Instead of using a loose culture of cells housed in a petri dish, he used the embryos of zebrafish (a type of minnow) to run his tests.

It was at this point that the research took a sudden turn in a different direction. There was no sign of kidney failure in the zebrafish when they were exposed to the aristolochic acid. The fish were, however, experiencing heart problems. Over time, Huang came to realize that the problems were in fact very similar to human heart failure.

“Starting from there,” Huang said, “we kind of designed this project to look for compounds that can arrest the heart failure in the fish – and that could be a drug for human heart failure as well.”

Using these zebrafish with their very humanlike heart problems as a model, Huang and the student researchers who worked with him began looking for drugs that could stop or slow heart failure. They’ve gone on trips to Taiwan as part of Huang’s biomedical study abroad course (BIOL 277), and have tested various native herbs to see if they show any ability to prevent heart failure.

In three years of work, they’ve so far managed to find one herb from hundreds tested that has shown promise, or “tested positive.” What Huang ultimately wants to find is one pure compound that’s responsible for the herb's ability to stop heart failure.

To do this, Huang and his students take the “crude extract” from the plant – basically the plant as it exists naturally - and divide the compounds from the extract into smaller fractions based on their chemical properties. They then test the fractions to see which one still tests positive. Once they find it, they divide that fraction into even smaller pieces, test, divide, test and so on.

“I feel like we are getting very close to identifying the pure compound that can rescue the heart failure,” Huang said.

Midway through this project, there came another split in the research. One of the compounds that was proving successful at stopping heart failure had a strange side effect: it caused the zebrafish to lose the pigment in their skin, essentially turning them into albinos. Curious as to why that was happening, Huang and his fellow researchers investigated.

What they found was that the new compound was preventing the proper functioning of menanocytes, which are the structures that produce melanin and in humans allow us to tan. Studying menanocytes is difficult, however, since they don’t grow well in a lab.

“In one of the experiments,” Huang said, “we had to use melanoma cells.”

What they accidentally found from this experiment was that the new drug didn’t just inhibit melanin pigment. It also prevented melanoma – skin cancer – from growing. This opened up an entirely new line of drug research: one aimed at finding a treatment for skin cancer.

“It’s still a puzzle to us,” Huang said. He and his fellow researchers don’t yet know how the compound prevents skin cancer from growing. However, they are very excited about the breakthrough and have begun working on the skin-lightening experiments as a separate project.

Neither project is complete. The heart failure drug is probably the closest, having gone on the longest. Even if a pure compound is found, however, it would have to be subjected to rigorous testing by the U.S. Food and Drug Administration before it could be approved for human use. The process could take as long as 20 years. A new drug, however, could be highly beneficial since heart failure is a complicated condition and none of the current drugs are 100 percent effective.

“There’s always a need for new drugs for heart failure,” Huang said.

Huang and his student researchers will continue with these two projects, and will continue traveling to Taiwan over J-term on a yearly basis to search for new herbs to test. In time, perhaps something new will come along.